Malignant gliomas are among the least curable and most chemo- and radioresistant of human tumors. In prior studies we and others established that expression of the multifunctional growth factor (SF/HGF) and its receptor c-Met in human gliomas increases significantly with tumor progression from low grade to malignant. We have found that SF/HGF protects human glioblastoma cells from cytotoxicity induced by DNA-damaging agents in vitro and protects against radiation-induced glioma cell apoptosis in vivo. We have established that the cytoprotective/anti-apoptotic action of c-Met activation by SF/HGF occurs, in part, through the PI3-kinase--> AKT second messenger pathway. The involvement of more downstream or parallel signaling pathways, gene expression, and biochemical effectors in the human glioma cytoprotective and anti-apoptotic response to SF/HGF remain unknown. This application proposes to identify specific molecular pathways through which SF/HGF stimulates chemo- and radio resistance in human glioblastoma cells. Aim #1 will identify novel differentially expressed gene products involved in SF/HGF-mediated cytoprotection of glioma cells. We will confirm and expand on our studies that have preliminarily implicated glioma cell- specific patterns of SF/HGF-induced gene expression in the cytoprotective mechanism. Aim #2 will determine the biochemical effector mechanisms of DNA damage-induced apoptosis and their inhibition by SF/HGF in human glioma cells. We will focus on sphingolipid signaling, death receptor signaling, mitochondrial damage, caspases and the regulators of caspase activation - IAPs and SMAC. Aim #3 will examine transcriptional regulators of SF/HGF-mediated glioma cell protection. We will determine how SF/HGF alters transcription factor activation/phosphorylation, nuclear translocation, DNA binding, and gene expression and determine the role of specific transcription factors in SF/HGF-mediated cytoprotection and other molecular/biochemical anti-apoptotic endpoints found in Aims #1 and #2. Aim #4 will determine if inhibiting endogenous autocrine SF/HGF:c-Met signaling or its downstream anti-apoptotic effectors identified in Aims #1-3 enhances the therapeutic response of human glioma xenografts to radiation and/or chemotherapy. These studies will determine mechanisms of human glioma chemo-and radio resistance identify new approaches to enhancing brain tumor cytotoxic therapy.